A lethal perinatal cardiac phenotype resulting from altered integrin function in cardiomyocytes

Background: Integrins are heterodimeric receptors that couple the extracellular matrix to intracellular signaling pathways and the cyoskeleton. Integrins are strain transducers and candidates for modulators or effectors of cardiac hypertrophy. Methods: To begin to probe this function, we have transgenically expressed a chimeric protein that alters integrin function in cardiomyocytes. The transgene (Tac-β_1D) consists of the biologically inert extracellular and transmembrane domain of the interleukin-2 receptor α subunit (Tac) fused to the cytoplasmic tail of the human β_1D integrin driven by the cardiac α-myosin heavy chain promoter. Transgene expression results in a severe, usually fatal, perinatal cardiac phenotype, characterized by initial electrocardiographic abnormalities followed by extensive myocyte loss, macrophage infiltration, and replacement fibrosis. Results: Expression of Tac-β_1D resulted in displacement of endogenous β_1D integrin from Z-lines and T-tubules, decreased expression of endogenous β_1D, and disrupted the fibronectin pericellular matrix. These results are consistent with an essential role for β₁ integrins in maintenance of cardiomyocyte viability and interaction with extracellular matrix. Conclusion: The appearance of conduction abnormalities before morphologic changes suggests that integrins are important in the development or maintenance of the conducting system of the heart.